1. Field of the Invention
This invention relates to a synthesis of CCI-779 or Proline CCI-779 (Temsirolimus) which is useful as an antineoplastic agent having the structure

It is stated to be effective in multiple applications, including inhibition of tumor growth, the treatment for multiple sclerosis and rheumatoid arthritis.
2. The Prior Arts
U.S. Pat. No. 7,202,256 disclosed methods for the synthesis of CCI-779 (Temsirolimus), providing two-step enzymatic process involving regiospecific acylation of rapamycin, using a microbial lipase and an activated ester derivative of 2,2-bis(hydroxymethyl)propionic acid in an organic solvent, followed by deprotection to obtain the CCI-779 (as shown in scheme 1). A number of drawbacks of the synthesis route depicted in scheme 1 are high-priced PdCl2 and poisonous trimethylboroxine.

A selective synthesis of 42-monoacylated product was previously conducted by reacting rapamycin 31,42-bis-silyl ether, and then the 42-sily ether protection group is selectively removed to provide rapamycin-OH-31-sily ether (U.S. Pat. No. 5,563,145). In addition, a regioselective process for the preparation of CCI-779 is also described in U.S. Pat. No. 6,277,983 (Scheme2). First, rapamycin (compound 4b) is treated with excess chlorotrimethylsilane to form rapamycin31,42-bis-trimethylsilyl ether (compound 5), and then 42-trimethylsilyl ether protection group is selectively removed in mild acid to provide rapamycin 42-OH-31-trimethylsilyl ether (compound 6). This free 42-OH was then acylated with 2,4,6-trichlorobenzyl mixed anhydride of 2,2,5-trimethyl[1,3-dioxane]-5-carboxylic acid (compound 7) at −15° C. for 16 h to give rapamycin 31-trimethylsilyl ether 42-ester (compound 8). Following treatment with mild acid for a certain period, CCI-779 can be isolated. 2,4,6-trichlorobenzyl chloride is irritant, moisture sensitive and costly.

Further, as below-depicted in Scheme 3, U.S. Pat. No. 7,153,957 disclose another method for the CCI-779. It can be prepared by the acylation of 31-silyl ether of rapamycin with the anhydride derived from the 2-phenylboronate acid to give rapamycin 31-silyl ether, 42-boronate. Thereafter, it is hydrolyzed under mild acid condition to form rapamycin 42-ester boronate. After being treated with a suitable diol, CCI-779 was obtained (Scheme 3). Mixed anhydride is not satisfactory for commercial scale synthesis because it can be kept stable only for 48 hr at −5˜0° C., not durable for longer time.
The present inventor has found the drawbacks of the prior art and invented the present process for the synthesis of Temsirolimus in a more economic way.
